The purpose of this study was to examine the effect of chlorinated amphetamines and related drugs on rat brain tryptophan hydroxylase. The time course of tryptophan hydroxylase depletion by p-chloromethamphetamine (PCMA) was followed in various brain regions. It was found that in regions rich in serotonergic nerve endings there was 30% inhibition after only 3 hours, and maximum inhibition occurred at approximately 24 hours. In brain regions containing cell bodies of serotonergic neurons inhibition of tryptophan hydroxylase was not seen until 24 to 48 hours after injection. Animals pretreated with chlorimipramine did not show tryptophan hydroxylase inhibition after PCMA treatment. Also, tyrosine hydroxylase activity was unaffected. These results suggest that PCMA is taken up at serotonergic nerve endings specifically, and has a neurotoxic effect. The delayed effect on cell body areas may be due to retrograde degeneration of axons and cell bodies. Chlorphentermine, an appetite suppressant structurally similar to PCMA, had no effect on tryptophan hydroxylase activity.